new methodology for the synthesis of thiobarbiturates mediated by manganese iii acetate

Malonate derivatives, key-step substrates for barbiturates synthesis [10,11], are also useful substrates for manganeseIII acetate-mediated reactions [12,13].. Our methodology allows synt

molecules

ISSN 1420-3049

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Communication

New Methodology for the Synthesis of Thiobarbiturates

Mediated by Manganese(III) Acetate

Ahlem Bouhlel, Christophe Curti and Patrice Vanelle *

Laboratoire de Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Institut de Chimie Radicalaire ICR, UMR 7273, Aix-Marseille Univ, CNRS, 27 Bd Jean Moulin, CS 30064,

13385 Marseille Cedex 05, France

* Author to whom correspondence should be addressed; E-Mail: patrice.vanelle@univ-amu.fr;

Tel.: +33-491-835-580; Fax: +33-491-794-677

Received: 15 March 2012; in revised form: 30 March 2012 / Accepted: 31 March 2012 /

Published: 10 April 2012

Abstract: A three step synthesis of various thiobarbiturate derivatives 17–24 was

established The first step is mediated by Mn(OAc)3, in order to generate a carbon-carbon

bond between a terminal alkene and malonate Derivatives 1–8 were obtained in

moderate to good yields under mild conditions This key step allows synthesis of a wide

variety of lipophilic thiobarbiturates, which could be tested for their anticonvulsive or anesthesic potential

Keywords: manganese(III) acetate; barbiturates; radical

1 Introduction

Manganese(III) acetate has been extensively explored during the past decades, and it remains an useful tool for carbon-carbon bond formation [1,2] Its specificity to carbonyl derivatives allows a wide variety of radical synthetic applications, as studied on acetoacetate [3], -ketoesters [4],

-ketonitriles [5,6] and -ketosulfones [7–9] Malonate derivatives, key-step substrates for barbiturates synthesis [10,11], are also useful substrates for manganese(III) acetate-mediated reactions [12,13]

In continuation of our research program centered on the design and synthesis of original molecules with pharmacological properties [14–18], we propose herein a manganese(III) acetate-mediated multistep synthesis of new original barbiturates

OPEN ACCESS

Barbiturate derivatives are a well-known pharmacological class with anticonvulsive, sedative and

anesthetic properties [19] Original barbiturates were also recently reported as matrix metalloproteinase

inhibitors with potent pharmacological applications against focal cerebral ischemia after acute

stroke [20] and cancer cells invasiveness inhibitors [21] Barbiturate derivatives also show

antitubercular [22], PPAR- agonist [23–25] and protein kinase C inhibitor [26] activities

The lipophilicity of barbiturates is an important parameter which enhances anesthetic onset [27] It

can be improved by replacing oxygen by a sulfur [28], as seen with the very short acting barbiturate

thiopenthal Substituents on the carbons of the barbituric acid scaffold also have a great influence

on the pharmacological activity [27,29] Our methodology allows synthesis of a wide variety of

substituted barbiturates, which could be tested for their anticonvulsive or anesthetic potentialities

2 Results and Discussion

Starting from malonate barbiturate precursors, reproducible methodology for synthesis of various and

highly functionalized derivatives was established As reported in previously described mechanisms [30],

Mn(OAc)3 and malonates in acetic acid form a Mn3+-enolate complex Mn3+ is reduced in Mn2+,

generating a carbon centered radical between carbonyl groups This radical reacts with terminal alkene,

generating a carbon-carbon bond

Depending on the malonate substituent, several reactions may occur and in order to investigate a

larger variety of barbiturate synthesis possibilities, we have studied three of them Results are reported

in Scheme 1

Scheme 1 Mn(OAc)3 reactivity towards various malonate derivatives

O

O

O

O CH 3

H 3 C

R R

O O

O O

Method A : Mn(OAc) 3

AcOH +

O

O

O

O CH3

H3C

CH 3

O

O

O

O CH3

H3C

O O

O

O CH3

H 3 C

R R O

O O

O CH3

H3C

R R

H3C

O O

O

O CH3

H3C

R R

Mn(OAc)3 Cu(OAc)2 AcOH

Mn(OAc)3 Cu(OAc)2 AcOH

+

+

R R

R R

R R

+

1 (11-49%)

3 (17-52%)

R = -CH3, -(CH2)3

-2 (10-36%)

4 (11-31%)

5 (47%)

6 (46%)

7 (26%)

8 (68%)

Method B : Mn(OAc)3 Cu(OAc) 2

As reported by Citterio and coworkers [31–33], benzylmalonate allowed synthesis of two

derivatives: Tetralines 1,3 from radical aromatic substitution, and elimination products 2,4 We have

previously reported different methods for optimizing yields of these two products [34] For conditions

favoring spirocyclic tetralin 1,3 formation, we divided up the Mn(OAc)3 to ensure moderate oxidizing

conditions (method A) Tetralins 1,3 were obtained as the major compound (49–52%) and alkenes 2,4

were observed as secondary products (10–11%) Stronger oxidative conditions [Cu(OAc)2 + Mn(OAc)3,

method B] afforded an increase in elimination products 2,4 (31–36%), while these conditions

drastically decreased yields of tetralines 1,3 (11–17%)

With methyl malonate, only elimination products 5–6 were obtained with moderate yields (46–47%)

With allyl malonate, cyclization generates a cyclopentane ring [35], and annulation products 7–8 were

synthesized (26–68%) These three different reactivities depend on the malonate substituents, and

allow access to a wide variety of substituted substrates for barbiturate synthesis

C-Functionalized malonates 1–8 thus obtained reacted with thiourea [36], forming thiobarbituric

scaffolds 9–16 in moderate to good yields (46–90%) Results are summarized in Scheme 2 and Table 1

Scheme 2 Thiobarbituric acid synthesis from malonates 1–8

H2N NH2

S +

R1 R2

O O

O O

R2

R1 S

DMSO

tBuOK

Table 1 Thiobarbituric acids 9–16 synthesis from malonates 1–8

Entry R 1 ,R 2 (malonate) Product Yields

3 C

H 3 C

O O

O O

H 3 C CH 3

NH HN

S

53%

2

O O

O

O CH3

H3C

CH3

CH3

3

CH3

10a / 10b

NH HN

S

46%

3

O O

O O

3

11

NH HN

S

64%

4

O O

O

O CH3

H 3 C

4

12

NH HN

S

88%

5

O O O

O CH3

H 3 C

CH 3

CH 3

H 3 C

3

CH 3

H 3 C

13a /13b

NH HN

S

75%

Table 1 Cont

Entry R1,R2 (malonate) Product Yields

6

O O O

O CH3

H3C

H 3 C

6

H3C

14

NH HN O O S

90%

7

O O

O

O CH3

H 3 C

CH 3

CH 3

7

CH 3

CH3

15

NH HN

S

70%

8

O O

O

O CH3

H3C

NH HN

S

54%

Finally, in order to synthesize intravenous administrable thiobarbiturates, each thiobarbituric acid

was turned into the corresponding salt with potassium hydroxide in isopropanol [37], as reported in

Scheme 3

Scheme 3 Thiobarbituric acid to thiobarbiturate salt formation

R2

R1

S - K +

R2

R1 S

9-16

KOH Isopropanol

17-24

3 Experimental

3.1 General

Microwave-assisted reactions were performed in a multimode microwave oven (ETHOS Synth Lab

Station, Ethos start, Milestone Inc., Shelton, CT, USA) Melting points were determined with

a B-540 Büchi melting point apparatus 1H-NMR (200 MHz) and 13C-NMR (50 MHz) spectra were

recorded on a Bruker ARX 200 spectrometer in CDCl3 or D2O at the Service interuniversitaire de

RMN de la Faculté de Pharmacie de Marseille The 1H-NMR chemical shifts are reported as parts per

million downfield from tetramethylsilane (Me4Si), and the 13C-NMR chemical shifts were referenced

to the solvent peaks: CDCl3 (76.9 ppm) or DMSO-d 6 (39.6 ppm) Absorptions are reported with the

following notations: s, singlet; bs, broad singlet; d, doublet; t, triplet; q, quartet; m, a more complex

multiplet or overlapping multiplets Elemental analysis and mass spectra which were run on

an API-QqToF mass spectrometer were carried out at the Spectropole de la Faculté des Sciences

Saint-Jérôme site Silica gel 60 (Merck, particle size 0.040–0.063 nm, 70–230 mesh ASTM) was used

for flash column chromatography TLC were performed on 5 cm × 10 cm aluminium plates coated

with silica gel 60 F-254 (Merck, Gernsteim, Germany) in an appropriate solvent

3.2 General Procedure for the Synthesis of Substituted Malonates 1–8

Method A: A solution of manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) in glacial acetic acid

(55 mL) was heated under microwave irradiation (200 W, 80 °C) for 15 min, until dissolution Then,

the reaction mixture was cooled down to 60 °C, and a solution of malonate (3.99 mmol, 1 equiv.) and

alkene (11.97 mmol, 3 equiv.) in glacial acetic acid (5 mL) was added The mixture was heated under

microwave irradiation (200 W, 80 °C) for 20 min Then, the reaction mixture was cooled down to 60 °C

once more, and a second portion of manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) was added

The mixture was heated under microwave irradiation (200 W, 80 °C) for 20 min The addition of

manganese(III) acetate dihydrate (1.68 mmol, 0.45 g) was repeated three times under the same

conditions every 20 min successively The reaction mixture was poured into cold water (100 mL), and

extracted with chloroform (3 × 70 mL) The organic extracts were collected, washed with saturated

aqueous NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, filtrated, and concentrated

under vacuum The crude product was purified by silica gel chromatography with ethyl

acetate/petroleum ether (0.5/9.5) to give corresponding compounds 1–4

Method B: A solution of manganese(III) acetate dihydrate (8.38 mmol, 2.24 g, 2.1 equiv.) and

copper(II) acetate monohydrate (3.99 mmol, 0.80 g, 1 equiv.) in glacial acetic acid (55 mL) was heated

under microwave irradiation (200 W, 80 °C) for 15 min, until dissolution Then, the reaction mixture

was cooled down to 60 °C, and a solution of malonate (3.99 mmol, 1 equiv.) and alkene (7.98 mmol,

3 equiv.) in glacial acetic acid (5 mL) was added The mixture was heated under microwave irradiation

(200 W, 80 °C) for 60 min The reaction mixture was poured into cold water (100 mL), and extracted

with chloroform (3 × 70 mL) The organic extracts were collected, washed with saturated aqueous

NaHCO3 (3 × 50 mL) and brine (3 × 50 mL), dried over MgSO4, filtrated, and concentrated under

vacuum The crude product was purified by silica gel chromatography with ethyl acetate/petroleum

ether (0.5/9.5) to give corresponding compounds 1–8

Diethyl 4,4-diethyl-3,4-dihydronaphthalene-2,2(1H)-dicarboxylate (1) Colorless oil; yields: 49%

(method A), 11% (method B); 1H-NMR (CDCl3) H 0.77 (t, J = 7.3, 6H, 2CH3), 1.22 (t, J = 7.2, 6H,

2CH3), 1.52–1.68 (m, 4H, 2CH2), 2.32 (s, 2H, CH2), 3.17 (s, 2H, CH2), 4.08–4.21 (m, 4H, 2CH2),

7.10–7.18 (m, 4H, 4CH) 13C-NMR (CDCl3) C 8.3 (2CH3),13.8 (2CH3), 33.1 (CH2), 33.3 (2CH2),

35.4 (CH2), 40.2 (C), 52.5 (C), 61.2 (2CH2), 125.5 (CH), 126.2 (CH), 126.5 (CH), 128.6 (CH), 134.2

(C), 141.5 (C), 172.9 (2C) HMRS (ESI): m/z calcd for C20H28O4 [M+H+]: 333.2060 Found: 333.2061

Diethyl 2-benzyl-2-(2-ethylbut-2-enyl)malonate (2a/2b) (50:50 inseparable mixture of Z/E isomers)

Colorless oil; yields: 10% (method A), 36% (method B); 1H-NMR (CDCl3) H 0.89–0.99 (m, 3H, CH3),

1.12–1.22 (m, 6H, 2CH3), 1.54–1.64 (m, 3H, CH3), 1.93–2.04 (m, 2H, CH2), 2.63 and 2.80 (s, 2H,

CH2), 3.24 and 3.26 (s, 2H, CH2), 4.03–4.15 (m, 4H, 2CH2), 5.26–5.42 (m, 1H, CH), 7.11–7.36 (m,

5H, 5CH) 13C-NMR (CDCl3) C 12.7 (CH3), 12.8 and 13.2 (CH3), 13.8 and 13.9 (2CH3), 23.3 and

29.6 (CH2), 33.5 and 40.6 (CH2), 39.1 and 39.2 (CH2), 58.9 and 59.0 (C), 61.1 (2CH2), 122.2 and

123.0 (CH), 126.7 (CH), 128.0 (2CH), 130.1 (2CH), 130.2 (C), 136.8 and 137.3 (C), 171.5 and 171.6

(2C) HMRS (ESI): m/z calcd for C20H28O4 [M+H+]: 333.2060 Found: 333.2063

Diethyl 2'H-spiro[cyclohexane-1,1'-naphtalene]-3',3'(4'H)-dicarboxylate (3) [34] Colorless oil;

yields: 52% (method A), 17% (method B); 1H-NMR (CDCl3) H 1.22 (t, J = 7.1, 6H, 2CH3), 1.47–1.80

(m, 10H, 5CH2), 2.46 (s, 2H, CH2), 3.19 (s, 2H, CH2), 4.14 (q, J = 7.1, 2H, CH2), 4.15 (q, J = 7.1, 2H,

CH2), 7.10–7.23 (m, 3H, 3CH), 7.35–7.39 (m, 1H, 1CH) 13C-NMR (CDCl3) C 13.9 (2CH3), 21.9

(2CH2), 25.9 (CH2), 34.9 (CH2), 35.6 (CH2), 36.8 (C), 39.6 (2CH2), 52.4 (C), 61.26 (2CH2), 125.8

(CH), 126.1 (CH), 126.5 (CH), 128.7 (CH), 133.4 (C), 144.0 (C), 171.8 (2C) Anal Calcd for

C21H28O4: C, 73.23; H, 8.19 Found: C, 73.40; H, 8.50

Diethyl 2-benzyl-2-(cyclohexenylmethyl)malonate (4) [34] Colorless oil; yields: 11% (method A), 31%

(method B); 1H-NMR (CDCl3) H 1.20 (t, J = 7.1, 6H, 2CH3), 1.55–1.59 (m, 4H, 2CH2), 1.90–2.00 (m,

4H, 2CH2), 2.58 (s, 2H, CH2), 3.26 (s, 2H, CH2), 4.12 (q, J = 7.1, 4H, 2CH2), 5.52 (s, 1H, 1CH),

7.11–7.24 (m, 5H, 5CH) 13C-NMR (CDCl3) C 13.9 (2CH3), 22.1 (CH2), 23.0 (CH2), 25.5 (CH2), 29.2

(CH2), 39.0 (CH2), 41.4 (CH2), 58.7 (C), 61.0 (2CH2), 126.4 (CH), 126.7 (CH), 128.0 (2CH), 130.1

(2CH), 133.1 (C), 136.7 (C), 171.4 (2C) Anal Calcd for C21H28O4: C, 73.23; H, 8.19 Found: C,

72.95; H, 8.35

Diethyl 2-(2-ethylbut-2-enyl)-2-methylmalonate (5a/5b) (50:50 inseparable mixture of Z/E isomers)

Colorless oil; yields: 47% (method B); 1H-NMR (CDCl3) H 0.81–0.93 (m, 3H, CH3), 1.14–1.21 (m,

6H, 2CH3), 1.27 (s, 3H, CH3), 1.48–1.53 (m, 3H, CH3), 1.65–1.96 (m, 2H, CH2), 2.57 and 2.71 (s, 2H,

CH2), 4.04–4.15 (m; 4H, 2CH2), 5.13 and 5.34 (m, 1H, 1CH) 13C-NMR (CDCl3) C 12.4 (CH3), 12.6

and 12.9 (CH3), 13.7 and 13.8 (CH3), 19.2 and 19.7 (CH3), 22.9 and 29.7 (CH2), 33.6 and 40.8 (CH2),

53.2 and 53.4 (C), 60.9 and 61.0 (2CH2), 122.4 and 123.4 (CH), 136.6 and 136.8 (C), 172.3 and 172.5

(2C) HMRS (ESI): m/z calcd for C14H24O4 [M+H+]: 257.1747 Found: 257.1743

Diethyl 2-(cyclohexenylmethyl)-2-methylmalonate (6) Colorless oil; yields: 46% (method B); 1H-NMR

(CDCl3) H 1.23 (t, J = 7.1 Hz, 6H, 2CH3), 1.34 (s, 3H, CH3), 1.44–1.58 (m, 4H, 2CH2), 1.73–2.03 (m,

4H, 2CH2), 2.58 (s, 2H, CH2), 4.15 (q, J = 7.1, 2CH2), 5.43 (s, 1H, 1CH) 13C-NMR (CDCl3) C 14.0

(2CH3), 19.9 (CH3), 22.0 (CH2), 22.9 (CH2), 25.4 (CH2), 29.2 (CH2), 43.7 (CH2), 53.3 (C), 61.1

(2CH2), 126.6 (CH), 132.9 (C), 172.6 (2C) HMRS (ESI): m/z calcd for C15H24O4 [M+H+]: 269.1747

Found: 269.1754

Diethyl 3,3-diethyl-4-methylenecyclopentane-1,1-dicarboxylate (7) Colorless oil; yields: 26% (method B);

1H-NMR (CDCl3) H 0.79 (t, J = 7.3, 6H, 2CH3), 1.24 (t, J = 7.1, 6H, 2CH3), 1.33–1.41 (m, 4H,

2CH2), 2.29 (s, 2H, CH2), 2.98–3.00 (m, 2H, CH2), 4.17 (q, J = 7.1, 4H, 2CH2), 4.65 (bs, 1H, CH),

4.95 (bs, 1H, CH) 13C-NMR (CDCl3) C 8.6 (2CH3), 14.0 (2CH3), 29.9 (2CH2), 41.8 (CH2), 43.3

(CH2), 48.5 (C), 57.3 (C), 61.4 (2CH2), 106.0 (CH2), 154.8 (C), 172.3 (2C) HMRS (ESI): m/z calcd

for C16H26O4 [M+H+]: 283.1904 Found: 283.1906

Diethyl 4-methylenespiro[4.5]decane-2,2-dicarboxylate (8) Colorless oil; yields: 68% (method B);

1H-NMR (CDCl3) H 1.22 (t, J = 7.2, 6H, 2CH3), 1.33–1.66 (m, 10H, 5CH2), 2.33 (s, 2H, CH2), 3.01

(bs, 2H, CH2), 4.15 (q, J = 7.1, 4H, 2CH2), 4.77 (bs, 1H, CH), 4.87 (bs, 1H, CH) 13C-NMR (CDCl3)

C 13.9 (2CH3), 23.2 (2CH2), 25.8 (CH2), 38.0 (2CH2), 40.8 (CH2), 42.6 (CH2), 45.6 (C), 57.9 (C),

61.4 (2CH2), 104.6 (CH2), 158.4 (C), 172.1 (2C) HMRS (ESI): m/z calcd for C17H26O4 [M+H+]:

295.1904 Found: 295.1903

3.3 General Procedure for the Synthesis of Thiobarbituric Acids 9–16

Thiourea (1.25 g, 16.38 mmol, 6 equiv.) was added to a solution of malonate 1–8 (2.73 mmol,

1 equiv.) in dry DMSO (3 mL) Then, a solution 1M of potassium tert-butoxide (0.67 g, 6.0 mmol,

2.2 equiv.) was added dropwise The solution was stirred for 4 h under inert atmosphere and at rt

(starting from malonates 1, 3, 7, 8) or at 50 °C (starting from malonates 2, 4, 5, 6) The solution was

diluted with ethyl acetate (15 mL) and washed with a solution of 1 N hydrochloric acid The layers

were separated and the aqueous phase was extracted with ethyl acetate The collected organic phase

was washed with brine, dried over anhydrous Na2SO4, filtered and the solvent was removed in vacuo

The residue was purified with column chromatography (CH2Cl2/petroleum ether, 8:2), affording the

corresponding thiobarbituric acids 9–16

4,4-Diethyl-2'-thioxo-3,4-dihydro-1H,2'H-spiro[naphthalene-2,5'-pyrimidine]-4',6'(1'H,3'H)-dione (9)

White solid; m.p 151 °C (cyclohexane);yields: 53% 1H-NMR (CDCl3) H 0.76 (t, J = 7.4, 6H, 2CH3),

1.67–1.80 (m, 4H, 2CH2), 2.23 (s, 2H, CH2), 3.28 (s, 2H, CH2), 7.12–7.36 (m, 4H, 4CH), 8.99 (bs,

2H) 13C-NMR (CDCl3) C 8.4 (2CH3), 31.5 (2CH2), 34.3 (CH2), 38.2 (CH2), 52.2 (C), 53.4 (C), 126.0

(CH), 126.2 (CH), 126.8 (CH), 128.5 (CH), 132.4 (C), 140.9 (C), 170.4 (2C), 176.0 (C) HMRS (ESI):

m/z calcd for C17H20N2O2S [M+H+]: 317.1318 Found: 317.1317

5-Benzyl-5-(2-ethylbut-2-enyl)-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (10a/10b) (50:50 inseparable

mixture of Z/E isomers) White solid; m.p 182 °C (cyclohexane); yields: 46% 1H-NMR (CDCl3) H

0.90–0.99 (m, 3H, CH3), 1.53–1.66 (m, 3H, CH3), 1.85–2.02 (m, 2H, CH2), 2.87 and 3.00 (s, 2H,

CH2), 3.30 and 3.38 (s, 2H, CH2), 5.19–5.30 and 5.41–5.52 (m, 1H, CH), 7.07–7.24 (m, 5H, 5CH),

8.84 (bs, 2H) 13C-NMR (CDCl3) C 12.6 and 13.0 (CH3), 13.4 and 13.7 (CH3), 23.4 and 29.9 (CH2),

39.1 and 44.9 (CH2), 45.0 and 45.2 (CH2), 58.0 and 59.0 (C), 124.6 and 124.8 (CH), 127.9 (CH), 128.9

(2CH), 129.5 and 129.6 (2CH), 134.2 and 134.3 (C), 134.7 and 135.7 (C), 169.6 (2C), 175.3 (C) m/z

calcd for C17H20N2O2S [M+H+]: 317.1318 Found: 317.1323

2"-Thioxo-2"H,4'H-dispiro[cyclohexane-1,1'-naphtalene-3',5"-pyrimidine]-4",6"(1"H,3"H)-dione (11)

White solid; m.p 200–202 °C (ethyl alcohol); yields: 64% 1H-NMR (CDCl3) H 1.49–1.84 (m, 10H,

5CH2), 2.35 (s, 2H, CH2), 3.31 (s, 2H, CH2), 7.12–7.41 (m, 4H, 4CH), 9.33 (bs, 2H, 2NH) 13C-NMR

(CDCl3) C 22.0 (2CH2), 25.7 (CH2), 33.6 (CH2), 37.8 (C), 38.1 (2CH2), 38.3 (CH2), 52.2 (C), 125.1

(CH), 126.1 (CH), 127.2 (CH), 128.5 (CH), 132.1 (C), 143.8 (C), 170.2 (2C), 176.0 (C) HMRS (ESI):

m/z calcd for C18H20N2O2S [M+H+]: 329.1318 Found: 329.1317

5-Benzyl-5-(cyclohexenylmethyl)-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (12) Colorless oil;

yields: 88% 1H-NMR (CDCl3) H 1.35–2.04 (m, 8H, 4CH2), 2.82 (s, 2H, CH2), 3.31 (s, 2H, CH2), 5.50

(s, 1H, 1CH), 7.13–7.26 (m, 5H, 5CH), 8.98 (bs, 2H, 2NH) 13C-NMR (CDCl3) C 21.9 (CH2), 22.8

(CH2), 23.6 (CH2), 29.8 (CH2), 44.5 (CH2), 47.6 (CH2), 58.9 (C), 127.7 (CH), 127.8 (CH), 128.8

(2CH), 129.5 (2CH), 131.5 (C), 134.3 (C), 169.7 (2C), 175.4 (C) HMRS (ESI): m/z calcd for

C18H20N2O2S [M+NH4+]: 346.1584 Found: 346.1579

5-(2-Ethylbut-2-enyl)-5-methyl-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (13a/13b) (50:50 inseparable

mixture of Z/E isomers) Colorless oil; yields: 75% 1H-NMR (CDCl3) H 0.87–0.97 (m, 3H, CH3),

1.54–1.61 (m, 3H, CH3), 1.57 (s, 3H, CH3), 1.80–2.01 (m, 2H, CH2), 2.70 and 2.82 (s, 2H, CH2), 5.18

and 5.47 (m, 1H, CH), 9.05 (bs, 2H, 2NH) 13C-NMR (CDCl3) C 12.6 and 13.0 (CH3), 13.3 and 13.9

(CH3), 23.1 and 23.3 (CH3), 23.5 and 29.9 (CH2), 40.4 and 46.2 (CH2), 51.0 and 51.9 (C), 124.5 and

125.0 (CH), 134.8 and 135.9 (C), 170.5 and 170.6 (2C), 176.0 (C) Anal Calcd for C11H16N2O2S: C,

54.98; H, 6.71; N, 11.66 Found: C, 55.15; H, 6.86; N, 11.63

5-(Cyclohexenylmethyl)-5-methyl-2-thioxo-dihydropyrimidine-4,6(1H,5H)-dione (14) White solid;

m.p 160–164 °C (ethyl alcohol); yields: 90% 1H-NMR (CDCl3) H 1.37–1.52 (m, 4H, 2CH2), 1.57

(s, 3H, CH3), 1.76–1.98 (m, 4H, 2CH2), 2.65 (s, 2H, CH2), 5.44 (s, 1H, 1CH), 9.61 (bs, 2H, 2NH)

13C-NMR (CDCl3) C 21.8 (CH2), 22.8 (CH2), 23.0 (CH3), 25.4 (CH2), 29.7 (CH2), 48.5 (CH2), 51.8

(C), 127.5 (CH), 131.6 (C), 170.9 (2C), 176.2 (C) HMRS (ESI): m/z calcd for C12H16N2O2S [M+H+]:

253.1005 Found: 253.1007

2,2-Diethyl-3-methylene-8-thioxo-7,9-diazaspiro[4.5]decane-6,10-dione (15) White solid; m.p

194–196 °C (cyclohexane); yields: 70% 1H-NMR (CDCl3) H 0.83 (t, J = 7.4, 6H, 2CH3), 1.43–1.70

(m, 4H, 2CH2), 2.27 (s, 2H, CH2), 3.03 (bs, 2H, CH2), 4.77 (bs, 1H, CH), 5.01 (bs, 1H, CH), 8.96 (bs,

2H, 2NH) 13C-NMR (CDCl3) C 8.7 (2CH3), 29.0 (2CH2), 44.4 (CH2), 47.2 (CH2), 49.9 (C), 54.3 (C),

107.4 (CH2), 153.4 (C), 170.7 (2C), 176.1 (C) HMRS (ESI): m/z calcd for C13H18N2O2S [M+NH4+]:

284.1427 Found: 284.1434

14-Methylene-3-thioxo-2,4-diazadispiro[5.1.5.2]pentadecane-1,5-dione (16) White solid; m.p 177 °C

(isopropanol); yields: 54% 1H-NMR (CDCl3) H 1.22–1.47 (m, 6H, 2CH3), 1.66–1.77 (m, 4H, 2CH2),

2.33 (s, 2H, CH2), 3.06 (s, 2H, CH2), 4.89–4.93 (m, 2H, CH2), 9.09 (bs, 2H, 2NH) 13C-NMR (CDCl3)

C 23.2 (2CH2), 25.7 (CH2), 37.5 (2CH2), 44.0 (CH2), 45.2 (CH2), 46.8 (C), 55.0 (C), 105.4 (CH2),

157.4 (C), 170.7 (2C), 176.2 (C) HMRS (ESI): m/z calcd for C14H18N2O2S [M+NH4+]: 296.1427

Found: 296.1422

3.4 General Procedure for Salification of Barbituric Acids to Barbiturate Potassium Salts 17–24

A suspension of potassium hydroxide (0.02 g, 0.36 mmol, 1 equiv.) in isopropanol (5 mL) was

stirred under inert atmosphere The corresponding barbituric acid 9–16 (0.36 mmol, 1 equiv.) was

added, and reaction was monitored by TLC until the barbituric acid disappeared Isopropanol was

removed in vacuo, and corresponding barbiturates 17–24 were obtained without further purification

Potassium

4,4-diethyl-4',6'-dioxo-1',3,4,6'-tetrahydro-1H,4'H-spiro[naphthalene-2,5'-pyrimidine]-2'-thiolate (17) White solid; m.p 161–163 °C (isopropanol); yields: 77%; 1H-NMR (D2O) H 0.72 (s,

3H, CH3), 0.99 (s, 3H, CH3), 1.42–1.79 (m, 4H, 2CH2), 2.38 (d, J = 15.4, 1H, CH2), 2.53 (d, J = 15.4,

1H, CH2), 3.13 (d, J = 16.4, 1H, CH2), 3.40 (d, J = 16.4, 1H, CH2), 7.35–7.41 (m, 4H, 4CH) 13C-NMR

(D2O) C 8.4 (CH3), 8.5 (CH3), 32.9 (CH2), 35.1 (CH2), 35.2 (CH2), 35.8 (CH2), 41.2 (C), 57.2 (C),

126.5 (CH), 127.0 (CH), 127.9 (CH), 129.1 (CH), 136.2 (C), 142.8 (C), 177.0 (2C), 178.9 (C) HMRS

(ESI): m/z calcd for C17H19N2O2S− M: 315.1173 Found: 315.1183

Potassium 5-benzyl-5-[2-ethylbut-2-en-1-yl]-4,6-thioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (18a/ 18b)

(50:50 inseparable mixture of Z/E isomers) White solid; m.p 142–144 °C (isopropanol); yields: 78%;

1H-NMR (D2O) H 0.98–1.05 (m, 3H, CH3), 1.61–1.73 (m, 3H, CH2), 1.93–2.12 (m, 2H, CH2), 2.89

and 3.01 (s, 2H, CH2), 3.28 and 3.38 (s, 2H, CH2), 5.11 and 5.51 (bs, 1H, 1CH), 7.22–7.39 (m, 5H,

5CH) 13C-NMR (D2O) C 12.6 and 12.7 (CH3), 13.2 and 13.3 (CH3), 23.6 and 29.8 (CH2), 39.3 and

44.8 (CH2), 45.0 and 45.9 (CH2), 57.6 (C), 122.7 and 123.8 (CH), 128.0 (CH), 129.1 (2CH), 129.9

(2CH), 135.9 (C), 138.0 (C), 172.9 (C), 179.6 (2C) HMRS (ESI): m/z calcd for C17H19N2O2S− M:

315.1173 Found: 315.1180

Potassium

4",6"-dioxo-1",6"-dihydro-4'H,4"H-dispiro[cyclohexane-1,1'-naphtalene-3',5"-pyrimidine]-2"-thiolate (19) White solid; m.p 216–218 °C (isopropanol); yields: 70%; 1H-NMR (D2O) H 1.38–2.25

(m, 10H, 5CH2), 2.40 (bs, 1H, CH2), 3.08–3.68 (m, 3H, CH2), 7.40–7.58 (m, 3H, 3CH), 7.72–7.78 (m,

1H, 1CH) 13C-NMR (D2O) C 22.1 (CH2), 22.4 (CH2), 26.0 (CH2), 35.8 (CH2), 37.6 (CH2), 37.7 (C),

38.2 (CH2), 42.0 (CH2), 56.9 (C), 126.8 (CH), 127.2 (CH), 127.3 (CH), 129.3 (CH), 135.3 (C), 144.7

(C), 176.5 (C), 178.8 (C), 181.5 (C) HMRS (ESI): m/z calcd for C18H19N2O2S− M: 327.1173 Found:

327.1184

Potassium 5-benzyl-5-(cyclohex-1-en-1-ylmethyl)-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (20)

White solid; m.p 143 °C (isopropanol); yields: 84% 1H-NMR (D2O) H 1.36–1.60 (m, 4H, 2CH2),

1.74–2.00 (m, 4H, 2CH2), 2.70 (s, 2H, CH2), 3.18 (s, 2H, CH2), 5.39 (s, 1H, 1CH), 7.06–7.11 (m, 2H,

2CH), 7.26–7.30 (m, 3H, 3CH) 13C-NMR (D2O) C 22.3 (CH2), 23.3 (CH2), 25.7 (CH2), 29.8 (CH2),

45.5 (CH2), 47.6 (CH2), 57.3 (C), 126.2 (CH), 127.8 (CH), 129.1 (2CH), 129.9 (2CH), 134.0 (C),

136.6 (C), 181.5 (2C), 192.6 (C) HMRS (ESI): m/z calcd for C18H19N2O2S− M: 327.1173 Found:

327.1173

Potassium 5-[2-ethylbut-2-en-1-yl]-5-methyl-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (21a/ 21b)

(50:50 inseparable mixture of Z/E isomers) White solid; m.p 174–176 °C (isopropanol); yields: 28%

1H-NMR (D2O) H 0.82–0.98 (m, 3H, CH3), 1.32–1.42 (m, 3H, CH3), 1.49–1.56 (m, 3H, CH3),

1.76–2.05 (m, 2H, CH2), 2.54–2.69 (m, 2H, CH2), 5.01 and 5.45 (bs, 1H, 1CH) 13C-NMR (D2O) C

12.8 and 13.0 (CH3), 13.2 and 14.0 (CH3), 21.0 and 22.7 (CH3), 23.7 and 30.2 (CH2), 38.5 and 44.8

(CH2), 56.7 and 57.0 (C), 123.1 and 123.8 (CH), 138.3 and 139.1 (C), 177.8 and 177.9 (C), 180.0 and

180.1 (C), 181.5 and 181.6 (C) HMRS (ESI): m/z calcd for C11H15N2O2S− M: 239.0860 Found:

239.0857

Potassium 5-(cyclohex-1-en-1-ylmethyl)-5-methyl-4,6-dioxo-1,4,5,6-tetrahydropyrimidine-2-thiolate (22)

White solid; m.p 177 °C (isopropanol); yields: 69% 1H-NMR (D2O) H 1.47 (s, 3H, CH3),

1.45–1.61 (m, 4H, 2CH2), 1.84–2.09 (m, 4H, 2CH2), 2.55 (s, 2H, CH2), 5.41 (s, 1H, 1CH) 13C-NMR

(D2O) C 22.4 (CH2), 22.5 (CH3), 23.3 (CH2), 25.7 (CH2), 29.6 (CH2), 47.4 (CH2), 56.8 (C), 126.7

(CH), 134.9 (C), 177.9 (2C), 181.6 (C) HMRS (ESI): m/z calcd for C12H15N2O2S− M: 251.0860

Found: 251.0859

Potassium 2,2-diethyl-3-methylene-6,10-dioxo-7,9-diazaspiro[4.5]dec-7-ene-8-thiolate (23) White

solid; decomp 270 °C (isopropanol); yields: 88% 1H-NMR (D2O) H 0.72–0.83 (m, 6H, 2CH3),

1.14–1.53 (m, 4H, 2CH2), 2.27 (s, 2H, CH2), 2.84 (d, J = 16.3, 1H, CH2), 3.04 (d, J = 16.3, 1H, CH2),

4.72 (bs, 1H, CH), 5.01 (bs, 1H, CH) 13C-NMR (D2O) C 8.6 (CH3), 8.7 (CH3), 30.5 (CH2), 31.0

(CH2), 41.7 (CH2), 45.0 (CH2), 49.1 (C), 62.5 (C), 105.8 (CH2), 157.2 (C), 176.7 (C), 179.1 (C), 182.1

(C) HMRS (ESI): m/z calcd for C13H17N2O2S− M: 265.1016 Found: 265.1025

Potassium 14-methylene-1,5-dioxo-2,4-diazaspiro[5.1.5.2]pentadec-2-ene-3-thiolate (24) White solid;

m.p 174–176 °C (isopropanol); yields: 53% 1H-NMR (D2O) H 1.13–1.65 (m, 10H, 5CH2), 2.25 (d,

J = 14.0, 1H, CH2), 2.40 (d, J = 14.0, 1H, CH2), 2.88 (d, J = 16.4, 1H, CH2), 3.04 (d, J = 16.4, 1H,

CH2), 4.86 (bs, CH), 4.96 (bs, CH) 13C-NMR (D2O) C 22.8 (CH2), 22.9 (CH2), 37.6 (CH2), 38.6

(CH2), 40.1 (CH2), 44.0 (CH2), 45.7 (C), 62.3 (C), 104.0 (CH2), 160.7 (C), 175.9 (C), 178.3 (C) 1C

not observed in these conditions HMRS (ESI): m/z calcd for C14H17N2O2S− M: 277.1016 Found:

277.1009

4 Conclusions

We have synthesized eight new functionalized thiobarbiturates by a three steps synthesis, thanks

to Mn(OAc)3 radical reactivity This methodology allows C-functionalization of barbituric acid with

a wide variety of scaffolds, such as aromatic, aliphatic and spirocyclic moieties Derivatives thus

obtained could be tested for their anesthetic potentialities, but also for targeting anticonvulsive leads

Acknowledgements

This work was supported by the Centre National de la Recherche Scientifique and Aix-Marseille

University We would like to express our thanks to V Remusat for recording the NMR spectra and

V Monnier for recording the mass spectra

References and Notes

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2 Demir, A.S.; Emrullahoglu, M Manganese(III) acetate: A versatile reagent in organic chemistry

Curr Org Synth 2007, 4, 321–350

3 Dombroski, M.A.; Snider, B.B Manganese(III)-Based oxidative free-radical Cyclizations of

γ,γ-bis(allylic) acetoacetates Tetrahedron 1992, 48, 1417–1426

4 Kates, S.A.; Dombroski, M.A.; Snider, B.B Manganese(III)-based oxidative free-radical

cyclization of unsaturated beta-keto esters, 1,3-diketones, and malonate diesters J Org Chem

1990, 55, 2427–2436

5 Chuang, C.-P.; Tsai, A.-I A novel oxidative free radical reaction between

2-amino-1,4-benzoquinones and benzoylacetonitriles Tetrahedron 2007, 63, 9712–9717